Critical role for αvβ6 integrin in enamel biomineralization

Mohazab, Leila; Koivisto, Leeni; Jiang, Guoqiao; Kytömäki, Leena; Haapasalo, Markus; Owen, Gethin; Wiebe, Colin; Xie, Yanshuang; Heikinheimo, Kristiina; Yoshida, Toshiyuki; Smith, Charles E.; Heino, Jyrki; Häkkinen, Lari; McKee, Marc D.; Larjava, Hannu

doi:10.1242/jcs.112599

Cited by 33 publications

(30 citation statements)

References 90 publications

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“…An Itgb6 null mouse exhibited a hypomineralized AI phenotype, with the loss of any ordered enamel prism arrangement (Mohazab et al, 2013). Accumulation of amelogenin in the enamel matrix and the presence of enamel pits were also noted (Mohazab et al, 2013).…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene AMELX, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and in vitro studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the possibility of novel treatments and prevention strategies for AI.

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Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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“…Further, incisors are abnormally white in absence of αvβ 6 integrins. Itgb6 −/− molar have also hypomineralized enamel as inferred by extensive wear at their occlusal surfaces and much faster rate of attrition compared to WT molars (Mohazab et al, 2013). …”

Section: Lessons From Incisors and Molars Structural Analysis In Knocmentioning

confidence: 99%

Comparative studies between mice molars and incisors are required to draw an overview of enamel structural complexity

et al. 2014

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In the field of dentistry, the murine incisor has long been considered as an outstanding model to study amelogenesis. However, it clearly appears that enamel from wild type mouse incisors and molars presents several structural differences. In incisor, exclusively radial enamel is observed. In molars, enamel displays a high level of complexity since the inner part is lamellar whereas the outer enamel shows radial and tangential structures. Recently, the serotonin 2B receptor (5-HT2BR) was shown to be involved in ameloblast function and enamel mineralization. The incisors from 5HT2BR knockout (KO) mice exhibit mineralization defects mostly in the outer maturation zone and porous matrix network in the inner zone. In the molars, the mutation affects both secretory and maturation stages of amelogenesis since pronounced alterations concern overall enamel structures. Molars from 5HT2BR KO mice display reduction in enamel thickness, alterations of inner enamel architecture including defects in Hunter-Schreger Bands arrangements, and altered maturation of the outer radial enamel. Differences of enamel structure were also observed between incisor and molar from other KO mice depleted for genes encoding enamel extracellular matrix proteins. Thus, upon mutation, enamel analysis based exclusively on incisor defects would be biased. In view of the functional relationship between enamel structure and tooth morphogenesis, identification of molecular actors involved in amelogenesis requires comparative studies between mice molars and incisors.

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“…It is able to activate transforming growth factor ␤1 (TGF-␤1) (8), and interestingly, mice deficient in ␤6 integrin have a normal life span but develop periodontal disease characterized by apical migration of the junctional epithelium on the tooth, periodontal inflammation, and alveolar bone resorption (5,9). These characteristics are suggested to be linked to poor TGF-␤1 activation, as TGF-␤1 is considered an anti-inflammatory cytokine in human PD (10).…”

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confidence: 99%

Periodontal Pathogens Invade Gingiva and Aortic Adventitia and Elicit Inflammasome Activation in αvβ6 Integrin-Deficient Mice

et al. 2015

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e The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin ␤6 ؊/؊ mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected Itg␤6؊/؊ mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotidebinding domain-and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in Itg␤6 ؊/؊ mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence in situ hybridization demonstrated active invasion of the aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens.

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Critical role for αvβ6 integrin in enamel biomineralization

Cited by 33 publications

References 90 publications

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Comparative studies between mice molars and incisors are required to draw an overview of enamel structural complexity

Periodontal Pathogens Invade Gingiva and Aortic Adventitia and Elicit Inflammasome Activation in αvβ6 Integrin-Deficient Mice

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